title: A reciprocal translocation dissects roles of Pax6 alternative promoters and upstream regulatory elements in the development of pancreas, brain, and eye.
abstract: Pax6 encodes a transcription factor with key roles in the development of the pancreas, central nervous system, and eye. Gene expression is orchestrated by several alternative promoters and enhancer elements that are distributed over several hundred kilobases. Here, we describe a reciprocal translocation, called 1Gso, which disrupts the integrity of transcripts arising from the 5'-most promoter, P0, and separates downstream promoters from enhancers active in pancreas and eye. Despite this fact, 1Gso animals exhibit none of the dominant Pax6 phenotypes, and the translocation complements recessive brain and craniofacial phenotypes. However, 1Gso fails to complement Pax6 recessive effects in lacrimal gland, conjunctiva, lens, and pancreas. The 1Gso animals also express a corneal phenotype that is related to but distinct from that expressed by Pax6 null mutants, and an abnormal density and organization of retinal ganglion cell axons; these phenotypes may be related to a modest upregulation of Pax6 expression from downstream promoters that we observed during development. Our investigation maps the activities of Pax6 alternative promoters including a novel one in developing tissues, confirms the phenotypic consequences of upstream enhancer disruption, and limits the likely effects of the P0 transcript null mutation to recessive abnormalities in the pancreas and specific structures of the eye.
authors.affiliation: Genome Biology Division, Lawrence Livermore National Laboratory, Livermore, California.
authors.forename: Colleen
authors.initials: C
authors.lastname: Elso
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Lu
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Weisner
authors.forename: Heather L
authors.initials: HL
authors.lastname: Thompson
authors.forename: Andrea
authors.initials: A
authors.lastname: Skinner
authors.forename: Ethan
authors.initials: E
authors.lastname: Carver
authors.forename: Lisa
authors.initials: L
authors.lastname: Stubbs
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology* / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005123:Eye / Q000196:embryology* / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010179:Pancreas / Q000196:embryology* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014178:Translocation, Genetic
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins
keywords: Pax6 gene regulation; alternative transcript function; chromosome rearrangement; eye development; pancreas development